Acquired Immune Deficiency Syndrome (AIDS) has become recognized as one of the most catastrophic diseases to confront humanity. The etiologic agent of this disease is a lymphotrophic retrovirus referred to as human immunodeficiency virus (HIV-1) (Science, 1988, 239, 573). Other retroviruses related to HIV-1 are also being identified. A few synthetic modified nucleosides have shown some promise in studies involving AIDS or AIDS-related complex (ARC) (Proc. Natl. Acad. Sci. USA, 1986, 83, 1911; J. Med. Chem., 1986, 29, 1561). These include 3'-azido-3'-deoxythymidine (AZT), 2',3'-dideoxycytidine (ddC), and 2',3'-dideoxyadenosine (ddA). The antiviral activity of these compounds is associated with their ability to inhibit, in their phosphorylated triphosphate forms, a key enzyme in the virus life cycle, i.e. reverse transcriptase (Proc. Natl. Acad. Sci. USA, 1987, 84, 2033). According to Broder and coworkers (Biochem. Pharmacol., 1987, 36, 1765), ddA is superior to ddC and AZT in terms of therapeutic index. However, the therapeutic efficacy of ddA is limited by its instability, both with respect to rapid enzymatic deamination by the ubiquitous mammalian enzyme, adenosine deaminase, and hydrolytic cleavage of the glycosidic bond. There is, therefore, a continuing need for novel congeners of ddA that continue to have antiretroviral activity against retroviruses such as the AIDS virus, but are more stable than ddA with respect to hydrolytic deamination of the 6-amino group and with respect to hydrolytic cleavage of the glycosidic linkage between the sugar and base moieties.
This invention has as its primary objective the fulfilling of the above need.
In particular, the objective of the present invention is the development of a series of congeners of the anti-AIDS compound, 2',3'-dideoxyadenosine, that involve strategic modification of the 2- and 8- positions such that they are stable and would therefore have markedly enhanced therapeutic potential.
A further objective is to provide an effective and direct route to the synthesis of functionalized congeners of the anti-AIDS compound, 2',3'-dideoxyadenosine.
A still further objective of the present invention is to provide therapeutic compositions containing the stable ddA congeners of the present invention.
The method and manner of accomplishing each of the above objectives of the invention will become apparent from the detailed description which follows.